The Morris K. Udall Parkinson's Disease Center of Excellence at Emory University will be a highly collaborative research program in which electrophysiologists, pharmacologists, and anatomists work together to study the effects of existing and new treatments for parkinsonism from a circuit perspective. The Center draws upon the proven ability of the basal ganglia research community at Emory to conduct translational research. Other Center assets will be its close ties to the clinical movement disorders group at Emory, the fact that a portion of the research will be carried out in primates at the Yerkes National Primate Research Center, and the Center's connection to an active population of patients with Parkinson's disease in the Atlanta area. Emory University is strongly committed to Parkinson's Disease research, and will support the Center by funding pilot grants and an invited speaker seminar series. The center will consist of four projects and two cores. Project 1 (Dr. Jaeger) will examine changes imposed by altered basal ganglia input onto thalamic neurons in the parkinsonian state. Project 2 (Dr. Wichmann) is a series of experiments in parkinsonian primates to compare the thalamic effects of pallidal and subthalamic nucleus inactivation and stimulation, as are commonly used to treat advanced parkinsonism in patients, with the goal of identifying changes in thalamic activity that are associated with the antiparkinsonian effects of these procedures. Project 3 (Dr. Miller) is a series of translational experiments that examine the use of orally active TrkB receptor agonists as symptomatic or neurorestorative treatment for Parkinson's disease in different rodent and primate models. Project 4 (Dr. Conn, Vanderbilt), investigates the effects of a series of novel subtype-selective muscarinic acetylcholine receptor antagonists and activators on basal ganglia activity, and on parkinsonism in rodent models. The projects will be supported by an administrative core (Core A, Dr. Wichmann, PI; Dr. DeLong, Co-1, Dr. Pearson, administrator), and by an anatomy and behavior core (Core B, Dr. Smith) which will provide immunohistochemistry and electron microscopy services to all of the center projects, and will conduct behavioral testing in MPTP-treated monkeys under project 3. PUBLIC HEALTH RELEVANCE: The Center will foster collaborative Parkinson's disease research, train young investigators, and educate the public about the disease. The Center's research will take a circuit level approach to explore synaptic and circuit interactions in the basal ganglia-thalamo-cortical network. It will increase our understanding of how existing therapies work, and develop and explore the mechanisms of action of new antiparkinsonian treatments. PROJECT 1 Principal Investigator: Dieter Jaeger, PhD Title: The Role of Mouse Motor Thalamus Relaying Basal Ganglia Outflow Description (provided by applicant): We will examine how the motor thalamus in mouse models of Parkinson's disease (PD) Is Involved In transmitting Parkinsonian activity patterns generated In the basal ganglia to the cerebral cortex. We will use simultaneous electrophysiological recordings from basal ganglia, thalamus, and cortex In anesthetized and awake mice to determine the presence of pathological activity patterns, and their relations between structures. One strength of the proposal consists of the use of in vivo intracellular thalamic recordings, which will allow us to examine the hypothesis that strong basal ganglia bursting activity observed In PD will trigger post inhibitory rebound bursting In thalamus. Previous work suggests that such bursting in the basal ganglia Is one of the characteristics of pathological activity patterns in PD, but the transmission of this activity through thalamus to cortex remains unclear. We will carry out a detailed analysis of the specific mechanisms of synaptic integration in motor thalamus of the mouse In the brain slice preparation, where we test the control of action potential initiation by Parkinsonian patterns of Input. Finally, we will determine whether pharmacological compounds known to Interact with thalamic cellular properties (M1 and M4 muscarinic receptor agonists or antagonists or selective Cav3 calcium channel blockers) can be used to reduce the transmission of pathological activity from the basal ganglia through thalamus to cortex. This project is tightly Integrated with the other projects of the overall Emory Udall Center grant application: We share the focus on thalamic processing with project 2, where it will be examined In primates rendered Parkinsonian with MPTP. We share the VMAT2L0 mouse model of PD with project 3, where it will be used to determine possible neuroprotective treatment strategies. Our analysis of pathological electrical activity patterns In the VMAT2L0 mouse developed by Dr. Miller at Emory will aid in the validation of this model. We obtain the pharmacological compounds to be tested for specific effect on thalamic processing through our interactions with project 4. These compounds mentioned above are promising novel specific receptor agonists and antagonists as well as channel blockers that are not otherwise available Public Health Relevance: The public health relevance of this project is the study of novel treatments for Parkinson's disease that target the motor thalamus. In addition, the expected results will help us to better understand how much transgenic mouse models of Parkinson's disease repeat the same pathological activity patterns in the brain as seen in human patients, and to determine which mouse model can be best used for detailed treatment studies.